Bilirubin

Bilirubin pigment is a breakdown product of the haem moiety of haemoglobin (Fig. 16.2). It is produced at sites of red cell destruction (e.g. spleen) and circulates in the blood in an unconjugated water-insoluble form bound to albumin. In the liver it is conjugated to glucuronic acid by the enzyme glucuronyl transferase. Conjugated bilirubin is water-soluble and can therefore appear in the urine if the outflow of bile from the liver is interrupted; the patient’s urine then becomes stained with conjugated bilirubin. Bilirubin is converted by bacteria in the intestine to faecal urobilinogen (stercobilinogen), some of which is absorbed and then excreted, mostly in the bile to complete its enterohepatic circulation or, in only trace amounts normally, by the kidneys to appear in the urine as urobilinogen. Stercobilinogen is oxidised to stercobilin (faecal urobilin), the principal faecal pigment.

Fig. 16.2 Simplified pathways of bilirubin metabolism. Excessive breakdown of haemoglobin, as in haemolytic anaemias, will lead to increased biliary excretion of bilirubin. Biliary obstruction will cause regurgitation of conjugated water-soluble bilirubin into the blood which is then excreted in the urine, causing it to darken. Liver cell damage in hepatitis will cause impaired biliary excretion of urobilinogen and conjugated bilirubin; these are excreted in the urine, causing it to darken. The enterohepatic circulation, which involves urobilinogen, also returns cholic acid and chenodeoxycholic acid to the liver; this enhances bile secretion.

In early or recovering viral hepatitis, impaired biliary excretion results in preformed stercobilinogen appearing in the urine in excess as urobilinogen; this is one sensitive marker of early liver injury. In well-established biliary obstruction, the urinary urobilinogen concentration falls, because the cessation of biliary excretion into the gut results in sustained absence of synthesis of faecal urobilinogen.

Enzymes

In liver cell injury, damage to the membranes of cells and their organelles allows intracellular enzymes to leak into the blood, where the elevated concentrations can be measured. Examples include ALT, AST and GGT. Their diagnostic usefulness is summarised in Table 16.1.

The enzyme alkaline phosphatase is normally present in bile. Obstruction to the flow of bile, by gallstones for example, causes regurgitation of alkaline phosphatase into the blood, resulting in increased serum concentrations.

Many of these enzymes are not exclusively specific to the liver; therefore the results of diagnostic serum assays need careful interpretation.

Albumin

Albumin is a major serum protein synthesised by the liver cells. It has a relatively long half-life, compared to that of clotting factors (see below), so liver damage has to persist before decreased serum levels are found. In chronic liver disease, such as cirrhosis, a low serum albumin concentration is an important manifestation of liver failure, which results in peripheral oedema and contributes to the presence of ascites due to a reduction in plasma oncotic pressure.

Clotting factors

Liver cells synthesise the vitamin K-dependent clotting factors, deficiency of which results in a bleeding tendency. This can be detected in the laboratory by measuring the prothrombin time. A prolonged bleeding and prothrombin time is a further manifestation of liver failure and, because these clotting factors have a relatively short half-life, deficiency may be found quite early in the course of the illness. The prothrombin time should be measured before performing a liver biopsy or undertaking surgery on a patient with liver disease to avoid the risk of unexpected haemorrhage. These clotting factor deficiencies can be corrected by administration of high doses of vitamin K or of the clotting factors themselves.

Pre-hepatic jaundice

The main cause of pre-hepatic jaundice is haemolysis, due for example to hereditary spherocytosis or autoimmune red cell destruction (see Ch. 23). In these conditions there is excessive production of bilirubin from the haemoglobin released from lysed red cells. Because the excess bilirubin is unconjugated, it is not excretable in the urine; the urine colour is normal (hence the synonym ‘acholuric jaundice’). The bile, however, may contain so much bilirubin that there is a risk of pigment gallstone formation.

Intrahepatic jaundice

Hepatic disorders in which jaundice may be a feature include:

In these conditions there is accumulation of bilirubin within the liver (intrahepatic cholestasis), often histologically evident in biopsies as plugs of bile pigment distending canaliculi. The excess bilirubin is predominantly conjugated, is therefore water soluble and is excreted in the urine, causing darkening; this is a simple but diagnostically useful observation.

Post-hepatic jaundice

Obstruction of the extrahepatic bile ducts is an important cause of jaundice necessitating urgent investigation and alleviation in order to prevent serious damage to the liver. Important causes are:

As with intrahepatic causes, some of which also directly interfere with biliary drainage (e.g. primary biliary cirrhosis, sclerosing cholangitis), the excess bilirubin is conjugated and darkens the urine. Conversely, the patient’s faeces are pale. Pruritus is a common and troublesome symptom, probably due to bile salt accumulation.

Aetiology

The major causes of acute liver injury are:

Direct physical injury to the liver, such as laceration in a road traffic accident, is another important form of acute liver injury, but the focal nature of the injury contrasts with the diffuse injury produced by the agents listed above. Recovery from acute liver injury, focal or diffuse, is attributable to the capacity of the organ for cellular regeneration.

Clinicopathological features

The clinical and laboratory manifestations of acute liver injury are:

Most of the signs and symptoms of acute liver damage are predictable from the known functions of the liver. The best known is jaundice (or icterus) due to failure of the liver to secrete bile at the rate at which it is formed in the body from the destruction of red cells. Severe acute liver damage can lead to bruising and haemorrhage, due to clotting factor deficiency, and coma due to the accumulation of toxic metabolites that mimic neurotransmitters (‘false neurotransmitters’).

Laboratory investigations

Laboratory investigations will reveal evidence of liver cell damage, in that there will be elevated levels of serum enzymes, particularly the transaminases, and bilirubin. Liver cell damage results in some impairment of bilirubin conjugation, but also failure to excrete conjugated bilirubin and any stercobilinogen absorbed from the gut. Consequently, the urine is darkened by the presence of excess conjugated bilirubin and urobilin (derived by oxidation from urobilinogen) that cannot be excreted by the liver (Fig. 16.2). Eventually, as the liver damage persists, urobilinogen disappears from the urine because little or no bilirubin is being excreted by the liver. Jaundice due to bile duct obstruction—commonly by gallstones—also results in dark urine due to excess conjugated bilirubin that cannot be excreted by the liver; urobilinogen is usually absent, unless the obstruction is of very recent onset or intermittent, because no bilirubin reaches the intestine. Examination of urine and faeces (for colour) can therefore assist in the differential diagnosis of jaundice (Table 16.2).

Table 16.2Differential diagnosis of jaundice from bile abnormalities in urine and faeces, and from serum

Histology

In almost all cases of acute liver injury there will be liver cell degeneration or death and an inflammatory reaction. Superimposed on this uniform reaction to acute injury are, in many cases, diagnostic changes specific to the causative agent.

Also evident in liver biopsies will be the pattern of cell damage, from which the prognosis can be deduced (Fig. 16.3):

Fig. 16.3 Patterns of liver cell death and their clinicopathological significance. Death of the liver cells immediately surrounding central veins denotes cardiac failure, some other impediment to venous drainage, or some toxic cause (e.g. paracetamol overdose). Bridging necrosis (in acinar zone 3) is a feature of severe hepatitis. Interface hepatitis is death of liver cells at the margin of the portal tracts; this is a feature of chronic hepatitis due to a variety of causes. Apoptotic death of single cells is typical of acute viral hepatitis.

Hepatitis viruses

The main hepatitis viruses (Table 16.3) are:

Table 16.3Hepatitis viruses: their characteristics and associated diseases (delta agent, a defective virus, is not included)

These hepatitis viruses are immunologically distinct. Infection usually confers life-long immunity to the infecting virus but not to the others.

The clinical features range from a trivial illness without jaundice (anicteric hepatitis) which may escape detection (this is a common result of HAV infection) to a more significant illness with jaundice and other clinical evidence of disturbed liver function. Sometimes the illness is dominated by jaundice, with little elevation of serum transaminases (cholestatic hepatitis). Severe infection leads to overt liver failure.

Yellow fever, caused by a group B arbovirus, shares many clinical and histological features with the illness usually designated viral hepatitis, but it is not normally included within this group for the purposes of description, mainly because its geographical distribution is very restricted.

The liver may also become infected by many other viruses, but these are not regarded as ‘hepatitis viruses’ because the infection is not confined to the liver. Examples include:

Hepatitis B virus

The main characteristics of hepatitis B are:

• spread by blood, blood-contaminated instruments, blood products and venereally

• relatively long incubation period

• liver damage by antiviral immune reaction

• carrier state exists

• relatively serious infection.

Infection by HBV used to be called ‘serum hepatitis’ because it was known to be transmitted by blood and blood products. This is because infected, but apparently healthy, individuals can carry the virus in their blood and pass it on to others by the transfusion of blood or its products. This mode of transmission is much less common now that blood donors are screened by testing for the presence of the virus. However, the term ‘serum hepatitis’ has been abandoned because it misleadingly excludes transmission of the virus by other methods, notably venereally; the disease is often transmitted between homosexual males. HBV can also be transmitted by contaminated needles, such as may be used for tattooing or by drug addicts. There is a relatively high incidence of the carrier state in underdeveloped countries and the virus can be transmitted vertically from mother to child—in utero, during delivery or through intimate post-natal contact.

Specific diagnosis is made by seeking the hepatitis B surface antigen (HBsAg, formerly known as ‘Australia antigen’ because it was first detected in the serum of an Australian aborigine). The presence of the ‘e’ antigen (HBeAg) in the patient’s serum indicates active viral replication.

HBV produces liver cell damage not by a direct cytopathic effect but by causing viral antigens to appear on the cell surface (HBsAg); these are then recognised by the body’s immune system and the infected liver cells are destroyed (Fig. 16.4). Thus, if immunity is generally impaired or there is specific tolerance to the antigen, the virus can survive in the liver cells without causing damage; such patients become asymptomatic carriers of the virus and their body fluids are a hazard to other individuals. Liver biopsies of HBV-infected carriers show that the liver cells have a ground-glass texture to their cytoplasm due to the abundance of virus particles.

Fig. 16.4 Comparison of the pathogenesis of HAV and HBV hepatitis. The A virus, in contrast to the B virus, appears to be directly cytopathic. The B virus evokes liver cell injury by causing viral antigens to be expressed on the liver cell surface (HBsAg, hepatitis B surface antigen). The infected cells are eliminated immunologically, but an asymptomatic carrier state can ensue in the absence of specific immunity. The pathogenesis of other hepatitis viral infections is less certain.

HBV infection is much more serious than HAV. Infection is more likely to produce a clinical illness and jaundice, and it is more likely to result in long-term sequelae such as chronic hepatitis and cirrhosis, or even death due to fulminating acute infection causing extensive hepatic necrosis. HBV is also involved in the pathogenesis of liver cell carcinoma.

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